Cerebrovascular mortality: trend and seasonality in Brazilian capitals, 2000–2019

ABSTRACT OBJECTIVE To evaluate the trend and seasonality of cerebrovascular mortality rates in the adult population of Brazilian capitals from 2000 to 2019. METHODS This is an ecological and descriptive study of a time series of mortality due to cerebrovascular causes in adults (≥ 18 years) living in Brazilian capitals from 2000 to 2019, based on the Brazilian Mortality Information System. Descriptive statistical techniques were applied in the exploratory analysis of data and in the summary of specific, standardized rates and ratios by sociodemographic characteristics. The jointpoint regression model was used to estimate the trend of cerebrovascular mortality rates by gender, age groups, and geographic regions. The seasonal variability of rates by geographic regions was estimated using the generalized additive model by smoothing cubic splines. RESULTS People aged over 60 years comprised 77% of all cerebrovascular deaths. Women (52%), white individuals (47%), single people (59%), and those with low schooling (57%, elementary school) predominated in our sample. Recife (20/1,000 inhab.) and Vitória (16/1,000 inhab.) showed the highest crude mortality rates. Recife (49/10,000 inhab.) and Palmas (47/10,000 inhab.) prevailed after we applied standardized rates. Cerebrovascular mortality rates in Brazil show a favorable declining trend for adults of all genders. Seasonality influenced rate increase from July to August in almost all region capitals, except in the North, which rose in March, April, and May. CONCLUSIONS Deaths due to cerebrovascular causes prevailed in older single adults with low schooling. The trend showed a tendency to decline and winter, the greatest risk. Regional differences can support decision-makers in implementing public policies to reduce cerebrovascular mortality.

Similarly, CBVD remain among the leading causes of death in Brazil, with a variable evolution in their trend over the last 30 years.Their spatial distribution also behaved unevenly in the country, with greater decreases in mortality rates in states with greater economic development.However, populations with low development indicators showed the greatest negative impacts [2][3][4] .
Epidemiological studies have contributed to the understanding and analysis of CBVD factors and determinants and to the support of policies, projects, and programs to promote health and prevent diseases.Thus, they better control this type of disease and reduce spending on specialized treatments and the psychological disorders of patients and families, especially in urban areas, which concentrate most of the population both worldwide and in Brazil (84% of the Brazilian population resides in urban areas and 24% in its capitals) [5][6][7] .In turn, metropolitan regions in Brazil have higher health coverage and better mortality records, enabling analyses in these areas to be representative of the population's health condition 7,8 .
Studies on CBVD mortality often focus on trend analyses associated with epidemiological and sociodemographic profiles but few publications have considered their seasonal variability [2][3][4]7 . Th impacts of temperature on cerebrovascular mortality have been widely documented.Epidemiological evidence suggests a strong U-or V-shaped relation between temperature and number of deaths, confirming the hypothesis that mortality progressively increases at extreme temperatures, both high and low 9 .The involved pathophysiological mechanisms, although still only partially understood, depend on individuals' hydration state, sympathetic autonomic nervous system reactivity, activation of the renin-angiotensin-aldosterone system, and systemic inflammatory responses, which, together with other multiple risk factors (hypertension, obesity, diabetes mellitus, age, hypercholesterolemia, smoking, alcohol use, etc.), act negatively contributing to cause stroke 9 .
The analysis of the seasonal component, which directly impacts the exposed population, adds knowledge about the behavior and evolution of this disease in different periods of the year and configures a relevant indicator to predict and adopt control measures, especially in the current scenario of climate change, in which the great heterogeneity, complexity, and social, ecological, and climatic diversity of Brazilian municipalities and regions 10 brings numerous challenges and impacts on the population's health.
In this perspective, this study aimed to evaluate the trend and seasonality characteristics of CBVD mortality in adults aged over 18 years living in Brazilian capitals from 2000 to 2019 to update this epidemiological profile and provide objective and useful information to assist health decision-making.In 2010, the total population aged 18 years and above living in Brazilian capitals totaled 33,423,348 inhabitants 6 .

This
Daily deaths (codes I60 to I69 according to the 10th International Classification of Diseases) and the population estimates of each year (on July 1st), projected by the Instituto Brasileiro de Geografia e Estatística (IBGE), were obtained from the Datasus Information System of the Ministry of Health 6 .Descriptive statistical techniques were applied for data exploratory analysis and summary by age, gender (male and female), race (white; Black-Brown; Indigenous-yellow), marital status (single = single, separated or widowed; married = married or in a consensual union), and schooling (low = no schooling or complete elementary school; medium = complete high school; higher schooling = complete higher education).Health indicators, such as the sociodemographic characteristic and mortality rate ratios, were evaluated according to the equations below: To adjust the confounding effect in the comparisons of rates in the period between capital populations according to age groups (18-29 [young adults], 30-59 [adults], and ≥ 60 [older adults]), the direct method of standardization was used 11 .The WHO world population (2000-2025) was adopted as our standard population, thus defined to reflect the average age structure of the world population (https://seer.cancer.gov/stdpopulations/world.who.html).
To estimate the trend of annual cerebrovascular mortality rates adjusted by gender, age groups, geographic regions, and Brazil, the jointpoint regression model was used 12 .This method selects the best fits from the sections of the continuous log-linear regression model and identifies the year(s) in which a trend change is produced, calculates the annual percent change (APC) between trend change points, and estimates the annual average percent change (AAPC) over the entire studied period.The number of junction points is obtained using the Monte Carlo permutation test (4,499 random permutations, significance level of 0.05).Once the k number of junction points is obtained, the different models are compared by the Bayesian Information Criterion.
Seasonality was also analyzed by geographic regions and the country.Descriptive statistical techniques were applied to observe the monthly and seasonal variability of the monthly time series of cerebrovascular mortality rate.Then, the mean values of the observations for each month of the year and their standard deviation with 95% confidence intervals were summarized. https://doi.org/10.11606/s1518-8787.2023057004813 For the temporal analysis, the generalized additive model (GAM) 13 was used to estimate the seasonal variability of monthly cerebrovascular mortality rates over the studied period by smoothing cubic splines.GAM is used to interpret nonlinear relationships between variables based on nonparametric functions called smoothing curves, in which the form of association is defined by the data themselves.The basic structure fitted to model seasonal variability corresponds to the following equation: in which g = additive binding function of the predictor variables; μ = mean value of monthly cerebrovascular mortality rates; α = intercept; s = smoothing spline function; month = month of the year; and time = number of months over the studied period.The models were evaluated by the adjustment coefficient (R 2 ), deviance explained (DE), cross generalized validation (GCV), and residue analysis 14 .Regarding the sociodemographic characteristics of the total number of studied deaths, 23% of individuals were aged under 60 years and 52% were women.Regarding race, white (47%) individuals showed a higher incidence rate than Black people (44%).Regarding marital status, 59% of individuals were single.Low schooling also prevailed, 19% of victims had no education and 57% only attended elementary school.
In Table 1, death ratios by gender show that, in general, the highest mortality occurred in men, who were also more prevalent in the Brazilian South, Southeast, and Northeast, unlike the North and Midwest, which showed a prevalence of women.We found a higher number of men aged from 30 to 59 years (death ratios by gender: Regarding mortality rates in the period, 13 capitals showed values above the national average, with the highest values in Recife (20/10,000 inhab.)and Vitória (16/10,000 inhab.).After standardization by age, results showed 20 capitals with values above the Brazilian average (24/10,000 inhab.),especially Recife (49/10,000 inhab.),Palmas (47/10,000 inhab.),Maceió (45/10,000 inhab.), and Aracaju (44/10,000 inhab.)(Table 1).
On the other hand, Figure 1 shows that annual cerebrovascular mortality rates in Brazilian capitals had a favorable trend to decline for all genders and age groups, despite patterns variability across the regions in the country (Table 2).The APC and AAPC results in this table suggest that the variation in the changes of rate trend values relates more to differences between age groups, after comparison between genders, also showing variations, although less pronounced. https://doi.org/10.11606/s1518-8787.2023057004813 Considering geographical distribution, the results in Table 2 show that the most significant reductions in the trend of average annual percentages over the studied period occurred in women aged 30 to 59 years in Southern (-5.8*[-6.4;-5.1]) and Southeastern (-4.4*[-4.7;-4.1]) capitals.In older adults (the group with the highest mortality rate among women, with rates above 31 deaths per 10,000 inhab.)(Figure 1C), the South (-4.0*[-.48;-3.2]) and Southeast (-3.3*[-3.6;-3.0]) also showed greater declines.The behavior among men was similar, with the largest significant reductions in AAPC at ages 30 to 59 years in Southern (-4.8*[-6.1;-3.4]) and Southeastern (-4.0*[-4.4;-3.6]) capitals, with rates above 42 deaths per 10,000 inhab.for older adults (Figure 1G).Northern and Northeastern capitals generally showed the smallest trend decreases.Regarding seasonal behavior, we can establish that the smoothing curves estimated by GAM of cerebrovascular mortality rates as a function of the studied period fit seasonal variability, with a pattern consistent with the intervals of average behavior of these rates  (Figure 2) in each region and Brazil.Table 3 shows the parameters after the application of generalized additive modeling.Note that the coefficients and effective degrees of freedom reflect the significance (p-value) if smoothing curve estimates, whose models showed reasonably adequate adjustments and prediction errors (GCV).
In general, mortality rates showed their highest values in the middle of each year, pointing to July and August as offering the most risk (i.e., the winter period in the Southern Hemisphere), except for the Brazilian North, whose capitals showed the highest peaks from March to May.On the other hand, February showed the lowest rates in all Brazilian capitals and thus in the country, except for the North and Midwest.
We should mention that, except for the Brazilian North, the summer months in the Southern Hemisphere (December to February) showed the lowest values of mortality rates due to CBVD.However, the autumn (April to June) and spring (September to November) month behave as transition periods (Figure 2).
Note: the blue solid line shows the smoothing curves of the behavior of mortality rates, estimated by the generalized additive models (GAM); whereas gray areas, 95% confidence intervals.Dashed and dotted lines with an error bar show mean behavior with the 95% confidence intervals of cerebrovascular mortality rates.

DISCUSSION
The higher frequency of deaths in older adults confirms that age is an important variable, often associated with multiple risk factors: cerebral vascular atherosclerosis, arterial hypertension (AHT), diabetes mellitus and metabolic syndrome, smoking, among others, whose evolution, together with genetic and immunological factors, contribute to the deterioration of individuals' health [1][2][3]14 . By ause of failures in adaptation responses due to internal changes in their regulatory systems, older adults are also more susceptible to environments with a high pollution load and extreme temperatures (minimum and maximum) 9 .
However, CBVD 9,15 also target young adults (with non-negligible mortality rates, as this study shows) despite a trend decline.Global incidence increases in those aged below 45 years have been reported, with the greatest impacts in low-and middle-income economies 15,16 .National studies have also characterized cerebrovascular morbidity and mortality in young people 14,17 , featuring among the foremost specific causes of death in those aged from 5 to 29 and 30 to 69 years 14 .Regarding risk factors, estimates suggest that the increased incidence of cerebrovascular episodes in young adults is related with the increasing trend of the aforementioned multiple risk factors.Other etiological factors that favor the occurrence of cerebrovascular episodes at these ages (also in Brazil) include HIV, sickle cell anemia, rheumatic heart disease, Chagas disease, tuberculosis, arterial dissection, and moyamoya disease [14][15][16] .
Several national studies have widely addressed the distribution of CBVD associated with gender, race, marital status, schooling, and years of potential life lost 4 .Lotufo et al. 18 , in a study on cerebrovascular mortality and race, found a predominance of Black And Brown individuals in Brazil, a result that contrasts with ours (in which white people showed the highest incidences), probably due to the age restriction (30-69 years) and short study period In total, three characteristics resulting from our analyses enable us to consider the protective effect of the hormone estrogen, which eventually contributes to decreasing the risk of vascular accidents, increasing life expectancy in women.Firstly, the predominance of mortality rates in men aged 30 to 59 years, compared to the same group in women (Figures 1B and 1F); secondly, the larger significant reductions in the mortality trend in women aged 30 to 59 years compared to men of the same age group (Figures 1B and 1F); and finally, the increase in mortality rates in women aged above 60 years compared to those under it (Figures 1B and 1C).Estrogen has been reported as positively affecting the human immune system, stimulating the production of antibodies, regulating lymphopoiesis, increasing HDL cholesterol levels, lowering LDL, and relaxing, softening, and dilating blood vessels.It also shows antioxidant, anti-inflammatory, and cell membrane stabilizing properties 15,19 .
Our findings agree with the literature regarding mortality rate trends.Despite the increase in the absolute number of cases and incidence in some Brazilian states and municipalities, in general, a decline in mortality rates took place from the end of the 20th century to 2017, being more accentuated in regions with greater socioeconomic development and technological advances in high-complexity medicine [2][3][4]7 , a behavior also observed on a global scale 1,16 . I this line, Southern and Southeastern capitals, with the highest economic growth, outlined the largest reductions in APC and AAPC, unlike the less economically developed North and Northeast regions.
On the other hand, the expansion of access to health services; the use of medications for acute cerebrovascular disease, chronic diseases, and lipid disorders; the greater control over modifiable risk factors; the increase in the number of intensive care units and availability of neuroimaging for diagnosis; and the implementation of promotion and prevention programs configure other factors that have favored the reduction of mortality rates 1,21,22 .
The National Health Survey (PNS) 23 showed risk factors for CBVD above the national average for the Brazilian North and Northeast: the proportion of adults who never had their blood pressure measured (NR = 7%; NER = 4.2%), hospitalizations for AHT (NR = 14.6%;NER = 16%), hospitalizations for diabetes (NR = Regarding seasonal behavior, the increase in rates in the middle of each year refers us, from the climatic point of view, to the fact that in the winter period, the risk of cerebrovascular mortality increases, specifically during July and August, except in Northern capitals.At this time of year, the country shows the lowest regional temperatures 26 .However, in Northern capitals (excluding their southern parts), the pattern of rate behavior differs, probably because the region shows no important minimum temperatures during this period, which are much higher (18° to 23°C) than in the rest of the country 26 .
During winter, we find multiple pathophysiological mechanisms linked to the occurrence of cardiovascular deaths: increased catecholamine levels, vasoconstriction, tachycardia, and blood pressure; hemoconcentration due to cold-related polyuria, and increased blood viscosity due to concentrations of coagulation factors, platelets, cholesterol, fibrinogen, and erythrocytes 9 .
Note that the risk of mortality persists in the summer, despite its lowest values.The increase in mortality in hot climate conditions is associated with extreme temperatures and heat waves, with more pronounced negative consequences in older adults 9 .Northern capitals behave unlike other Brazilian capitals as they follow the change in the climatic pattern, since September and October, the hottest months of the year in this region 27 , coincide with the lowest rates of cerebrovascular death, unlike other regions, in which rates decrease from December to February.However, the geographical location of capitals between the equatorial, tropical, and subtropical zones in Brazil suggests that the population, constantly exposed to environmental changes, adapts better to hot temperatures than to cold ones, regardless of other factors, which this this research ignored, that may determine this behavior.
In agreement with our results, both Keatinge et al. 27 (in several European regions) and Su et al. 28 (in 17 Chinese cities) reported a higher annual number of deaths and a relative risk of cold-related cardiovascular mortality, establishing regional differences and pointing to a small proportion of deaths unrelated to seasonal variability.
Silveira et al. 29 concluded that both low and high temperatures in Brazil add to the risk of cardiovascular mortality in most Brazilian capitals, with variations according to geographic location.In general, the authors observed a U-shaped exposure-response relationship, with more pronounced consequences in low temperatures and places with greater thermal amplitude.
Regarding the potential limitations of this research, we should point out that the use of secondary data, subject to different levels of quality related to underreporting and ill-defined causes, may have partially influenced our results.Thus, regarding scope, coverage, and veracity, studies confirm important advances in the quality of mortality data in Brazil, especially in areas with greater socioeconomic development 2 .Data generated by the Mortality Information System (SIM) can reproduce the spatiotemporal dynamics of mortality, generating subsidies and priorities for policies and actions to promote health 14 .Another limitation to be considered is that the types of cerebral vascular arteries remained unspecified, despite the different pathophysiological mechanisms between them.
Our grouping of data by region configures another limitation, which probably reduces an accurate capture of local mortality behaviors.However, we find that this study estimates the significant trend and seasonality changes, enabling us to synthesize characteristics related to cerebrovascular mortality of interest to public health in areas with a high population concentration and subject to the influence of common environmental, social, and economic factors. https://doi.org/10.11606/s1518-8787.2023057004813 We conclude that our findings enabled us to characterize the epidemiological and sociodemographic profile of Brazilian capitals and the Federal District regarding cerebrovascular mortality from 2000 to 2019, pointing to single older adults of all with low schooling as the most affected population and, therefore, with a higher degree of social vulnerability.Depending on the region, white (South, Southeast) and Black individuals (North, Northeast, and Midwest) show the highest incidence rates.In the evaluation of the mortality rate trend, although it has decreased over the period, its behavior remains concerning due to the multifactorial character of its origin and evolution.Seasonality analysis showed winter as the period of highest risk of mortality in the national territory.Regional differences enable the definition of priorities and subsidizing decision-makers with medium and long-term actions toward planning and implementing policies and programs to reduce, promote, and prevent cerebrovascular mortality.
However, this study emphasizes the need to further develop and broaden research considering other risk factors outside the scope of this study.
is an ecological and descriptive study of a time series of mortality due to cerebrovascular diseases occurring in the population (aged ≥ 18 years) living in the 26 Brazilian capitals and Federal District (DF) from 2000 to 2019.Capitals were grouped by geographic regions: South [SR]; Southeast [SER]; Northeast [NER]; North [NR]; and Midwest 2,6 .

a)
Ratio of deaths by gender = male female b) Ratio of deaths by race = white (Black + Brown) + (Indigenous + yellow) c) Ratio of deaths by marital status = married single d) Ratio of deaths by schooling = low schooling medium + higher schooling e) Mortality rate (period) = Total deaths by CBVD Population in 2010 + studied period (20 years) × 10,000 inhab.f) Mortality rate (annual) = Total annual deaths by CBVD Estimated population (July 1) × 10,000 inhab.g) Mortality rate (monthly) = Total monthly deaths by CBVD Estimated population (monthly) × 10,000 inhab.
AAPC: average annual percentage change.Note: A: women aged 18 to 29 years; B: women aged 30 to 59 years; C: women aged 60 years; D: women aged 18 years; E: men aged from 18 to 29 years; F: men aged from 30 to 59 years; G: men aged 60 years; H: men aged 18 years.

Figure 1 .
Figure 1.Trends in annual cerebrovascular mortality rates (per 10,000 inhabitants) in men and women according to age group.Brazil, 2000-2019.
Belém, and Salvador.Marital status behaved uniformly, with a predominance of single people.The highest indicators of low schooling prevailed in Teresina and Palmas, with a 9.22 and 7.24 death ratio per schooling, respectively.

Table 2 .
Trends of annual cerebrovascular mortality rates (per 10,000 inhabitants) in men and women, according to age group.Brazilian region capitals, 2000-2019.

Table 2 .
Trends of annual cerebrovascular mortality rates (per 10,000 inhabitants) in men and women, according to age group.Brazilian region capitals, 2000-2019.Continuation

Table 3 .
2stimates of generalized additive model (GAM) parameters by Brazilian regions.bythoseauthors.However, Dorlens et al.2reported the highest rates in older single men with low schooling from 1996 to 2015, results similar to ours.
2: coefficient of determination or adjustment of models; DE: deviation explained; GCV: generalized cross-validation; month: month of the year; time: number of months throughout the studied period.* Significant.https://doi.org/10.11606/s1518-8787.2023057004813chosen 22pan), Omama et al.22reported a decrease in the incidence rate trend of cerebrovascular diseases from 2008 to 2017 in those aged above and below 55 years of both genders.
25e et al.24found similar findings in SouthKorea (2011-2015), describing increased cerebrovascular mortality rates in regions with lower socioeconomic development and an association with overweight, alcohol consumption, number of hospital beds, and number of neuroimaging devices available to the population.Yanez et al.25also reported increases in poorer Colombian regions, with greater difficulties accessing pre-hospital and hospital health services and the correlation with AHT, obesity, and smoking.However, in the https://doi.org/10.11606/s1518-8787.2023057004813prefecture of Iwate (